Glucocorticoids Suprarenal - PowerPoint Presentation

Slide1

Glucocorticoids

Slide2

Suprarenal

glands - anatomy

Slide3

Adrenal

cortex - physiology

Zona

glomerulosa

Zona

fasciculata

Zona reticularis

Zona

glomerulosa

–

mineralocorticoids

production

- aldosteron

10 – 15%

of

tissue

,

controlled

by ATII a K

+

.

Zona

fasciculata

75%

of

tissue

,

controlled

by ACTH, „

stock

“

of

cholesterol,

its

releasing

and

transformation

to

cortizol

=

main

human

glucocorticoid

.

Zona

reticularis

10 – 15 %

of

tissue

–

androgens

,

gestagens

,

cortisol

production

.

Slide4

Adrenal

medulla -

physiologyA-cells – adrenaline

- 80 %

catecholamines

secreted to the blood. Adrenalin secretion based on n

Nerve impulse →physical and psychological stress (crisis situation) →alarm reaction → adaptation

stage → ↑ glucosis, lactate, free fatty acids

concentration

,

→

exhaustion

stage

.

N-

cells

–

noradrenaline

–

causes

contraction

of

blood

vessels

(

except

heart

vessels

),

thereby

↑

blood

pressure

.

Slide5

STRESS -

physiology

Adrenal medulla activation makes

changes

leaded

to organism survival in exceptional

conditions Cells produced hormons – colored by chrome

colors = chromafine = feochromocytesSource material

for

adrenal

medulla

hormones

synthesis

= dopamine, noradrenaline and adrenaline =

tyrosine,

created

from

phenylalanine

STRESS –

organism

reaction

to

burden

–

mental

(

fear

,

anger

),

physical

(

cold

, hot),

traumatic

,

exertion

–

hypoglycaemia

,

hypoxia

A –

ALARM STAGE

- Acetylcholine

is

released

from

presynaptic

nerve

fibres

terms

→

starts

catecholamines

secretion

from

feochromocytes

B - ↑ BP,

glycogenolysis

(

glycogen

breakdown

in

livers

and

muscles

to

glucose

=

energy

source

) →

hyperglycaemia

,

lipolysis

(

fatty

acids

release

from

fat

cells

,

fatty

acids

=

energy

source

) =

glucose

and

fatty

acids

preparation

to

muscular

work

„to

struggle

, to

escape

“.

C –

parallel

activation

of

system

CRH – ACTH –

cortisol

- ↑

cortisol

secretion

D -

ADAPTATION STAGE

–

Cortizol

–

encourages

gluconeogenesis

=

glucose

synthesis

(

also

after

exhaustion

of

glycogen

from

non-

sugar

substrates

–

amino

acids

, glycerol and

lactate

) and

lipolysis

(

see

above

) =

additional

„

secure

of

fuel

“

for

energy

expenditure

E–

EXHAUSTION STAGE

–

during

long and

heavy

stress –

depletion

of

cortisol

,

disruption

of

its

secretion

, (supra

renal

cortex

damage

) –

organism

collapse

→

hypotension

,

shock

,

heart

failure

.

NT –

neurotransmitters

, ANS –

autonomic

nervous

system

, S –

sympathetic

, PS –

parasympathetic

, BP –

blood

pressure

Slide6

Glucocorticoids

-

regulation

hypothalamus

hypophysis

Suprarenal

gland

CRH

corticoliberine

ACTH

corticotropine

cortisol

pyrogens

↓

BP

↓

glycaemia

ADH

histamine

pain

stress

+

-

-

+

+

+

+

+

+

+

+

+

Slide7

Endogenous

and

exogenous

cortisol

secretion

Resting – 20 – 25 mg/24 hoursStress: 10 times

higherMaximum: 6 – 8 hours

a.m

.

Exogenous

corticoids

usage

–

endogenous

secretion downturn

Slide8

Steroid

hormones

biosynthesis - biochemistry

Cholesterol

Pregnenolone

Progesterone

17

α

-OH -

pregnenolone

17

α

-OH - progesterone

DHEA

11-

deoxycorticosterone

11 -

deoxycortisol

androstendion

other

17 -

ketosteroids

corticosterone

aldosterone

Hydrocortisone

=

cortizol

cortizon

estrone

estradiol

testosterone

dihydrotestosterone

Precurzors

Intermediate

products

Mineralocorticoids

Glucocorticoids

Estrogens

Androgens

17

ketosteroids

20,22

desmolase

3

β

-

dehydrogenase

21-

β

hydroxylase

17

α

hydroxylase

17

α

hydroxylase

11-

β

hydroxylase

TRILOSTAN

METYRAPON

Slide9

Glucocorticoid

Mechanism

of

action

in

cellular level

Receptor

Specific

Receptor-hormon komplex

Receptor in cytoplasma –

slower

efekt

Slide10

Change

of

proteosynthesis

Mechanism

of

action

in

cellular

level

Specific

Slide11

Glucocorticoids

influence

sugar, fat and protein metabolism have anti-inflammatory

and

anti-

allergic

effect have immunosuppressive effect

(in many branches – in next slides) have antiproliferative

effectHydrocortisone (cortizol)

Slide12

reduced

glucose

uptake

and

reduced

glucose

utilisation

in

the

cell

Proteolysis

,

tissue

proteins

=

aminoacids

decomposition of

tissue proteins

↑

gluconeogenesis catabolism

(glucose formation

from non

sugar

residues)

↑ glycaemia

Connective tissue

muscle atrophy fibroblasts

growth stopping ↑ of

insulin secretion ↓

osteoblasts, ↑osteoclasts

↓collagen

synthesis↓Ca

resorption from

intestine

, kidneys (

osteoporosis) ↑

storage of glycogen

in the liver lipogenesis support,

lipolysis inhibition

fat deposition, redistribution

, ↑glycerol, aminoacids in

blood

GCs and sugar, fat and protein metabolism

Fats

:

↑

lipolysis

,

facilitation

of lipid absorption, fat

redistribution

Slide13

CNS:

Euphoria / psychotic disorder after high doses / depression

GIT:

Increasing formation of

HCl

and pepsin in the stomach

BLOOD:

↑

Tro

, Ery,

circul

.

↓

lymfocytes

,

↓

eosinofils

LUNGS:

↑ formation of

pulmonary

surfactant

HCl –

hydrochloric acid

Other

effects

Slide14

Permissive

effect

to:

-

D

evelopment

of organs of the fetus

-

D

evelopment

and maturation of intestinal enzymes

-

I

ncreases

the synthesis of surfactant in the lungs of the fetus

- S

uppresses

bone growth

Ions

- Decreased calcemia - Increased potassium loss

- Sodium and chloride retention

GCs

and

congenital developmental

defectsGK and ions

Slide15

Negative feedback on

the

hypothalamus

and

the

anterior

lobe

of

the

pituitary

gland

reduced

release

of

endogenous

glucocorticoids

Vazotropic

-

GCs

-

vaso

constriction, decrease of permeability of vessels, suppression of

edemaAt cell

level: in place of acute inflammation: decrease in migration and leucocyte activity   

in place of chronic inflammation: decrease proliferation of blood vessels and fibrosis    In place of

lymphoid tissue: decrease B and T lymphocyte expansionTowards

the mediators of

inflammation and immunological reaction:

Decrease of cytokine production and activity, decreased synthesis of PGs

Regulatory effects

Slide16

Anti-

inflammatory

– cascade inhibition of AA

glucocorticoids

Phospholipase

A2

A2

Membrane

phospholipids

Arachidonic

acid

lipoxygenase

cyclooxygenase

LEUKOTRIENS

PROSTAGLANDINS

PROSTACYCLINS

THROMBOXANS

inflammation

Fagycytosis

mobilisation

Blood

vessel

permeability

change

Inflammation

A-A

NSAID

Inh

. 5-LOX -

antileukotriens

lipocortins

eikosanoids

Slide17

Anti-

inflammatory

effectAA cascade

inhibition

Migration

and

leucocyte function disruption

Antibody production reduction

All types of inflammation regardless of origin

!

(

aseptic

,

viral

,

bacterial

,

parasitic

….)

Slide18

Immunosupressive

effect

Inhibition

of

antigen

recognition

Inhibition of the effector

phase of the

immune

response (cell

lysis

)

! CAUTION:

Inhibition

CELL MEDIATED

immunity

ANTIBODY

immunity

is affected

significantly less and in GSc

higher

doses

Slide19

Anti-

inflammatory

effectDecreased histamine release from

basophils

Inhibition

of the

formation of inflammatory mediators and allergic

reactions (cytokines, complement components,

kallikrein

...)

Slide20

Anti-

proliferative

effectBlock cell cycle

Induction

of

differentiation

GCs - lymphocyte disintegration (

acute and chronic lymphocytic leukemia

,

lymphomas

,

myelomas

)

Slide21

Effect

and equipotent

doses of CSs

Substance

Equip.dose

Anti

infl

.

effect

Mineral

.

effect

Cortisol

20 mg

1

1

Cortisone

25 mg

0,8

0,8

Prednisone

5 mg

4

0,8

Prednisolone

5 mg

4

0

Methylpredn

.

4 mg

5

0

Triamcinolone

4 mg

5-10

0

Dexamethasone

0,75 mg

25

0

Bethametasone

0,6 mg

25

0

Fludrocortisone

-

10

125

Slide22

GCs

effects

, anti-inflammatory, immunosupressive and other effects

Strong anti-inflammatory and immunosuppressive action

INHIBITION OF ACUTE AND CHRONIC DISEASE, INFLUENCE OF ALL TYPES OF

INFLAMMATORY

REACTIONSInhibition of healing repair processes, prevention of graft rejectionMineralocorticoid effects: sodium retention, potassium depletionBlood and lymphatic system: ↓ lymphocytes, ↓ eosinophils in circulation,

their redistribution to BM, spleen, LN, ↑ platelets, erythrocytes and HB

Kidneys: glucocorticoids maintain the ability of the kidneys to secrete water, retain glomerular filtration, tubular resorption, prevent the transfer of water to cells and maintain extracellular fluid volumeHeart and vessels: allow for increased sensitivity to the vasoactive effect of catecholamines and ATII, increased myocardial contractility and vascular toneCNS: mood regulation,

strong

insomnia

GIT: increased secretion of HCL and pepsin, increased absorption of lipids from the intestine, decreased absorption of Ca

Bone metabolism: osteoporosis (metabolism of Ca, P, collagen synthesis and degradation, osteoblasts / cl

asts

)

Pulmonary surfactant: cortisol - an endocrine stimulant for pulmonary surfactant formation

Slide23

Systemically

administered GCs1-4

times

efficient

than cortisol

prednisolone, prednisonehydrokortisone

5-15times efficient than

cortisol

methylprednisolone

(

Solu-Medrol

)

triamcinolone

paramethasone

fluprednisolone

approx

30times

efficient

than cortisol

bethametasonedexamethasone

Short

term

acting

Medium term

acting

Long term

acting

(

stronger

axis

supression

)

Slide24

Glucocorticoids

therapeutical

regimen

types

Short

term

application

of

high

doses

A)

single

(2-4 g

methylprednisolone

)

 

Polytraumatas

,

septic

, toxic

shock

 

Hydrocortisone 30 mg / kg

B)

repeated

(methylprednisolone, hydrocortisone

, dexamethasone) 

Anaphyl. Shock, status

asthmaticus, hypoglycemic coma ...

  Duration up to 48

hours  Exceptionally

up to 7 days

Slide25

C)

Pulse therapy

  Short-term infusions for several days

  Originally in transplant rejection

  Today predominantly in immune-mediated diseases resistant to

standard therapy

D) Prolonged therapy

  In most

branches

  Primarily for anti-inflammatory and immunosuppressive effects

  Dosage and length depend

s

on the current stat

us

of the patient

  Strength differences, duration and frequency

of

adverse

e

ffects

  No hydrocortisone with respect to

mineralo

corticoid

a

ctivity

Glucocorticoids

therapeutical

regimen types

Slide26

Glucocorticoids

–

adverse

events

Before

therapy

start:

potential

infection

elimination

fasting

glycaemia

diabetes

compensation

preventive

application

of

D vitamine

anti-

ulcer

treatment

Slide27

During

the

therapy

:

DM monitoring

compensation

monitoring of mental

state

myopathy

and

osteporosis

prevention

(K, Ca,

rehab

.,

exercise

)

thromboembolic

prevention

consultation

the centre

for

growth hormone

treatment in

pediatric medicine

Glucocorticoids

– adverse events

Slide28

Prevention

-

Application of the lowest effective dose

-

If possible local applications

Combination with other drugs

C

ircadia

n

therapy / alternating therapy

Minimizing the use of depot

medication

(circadian rhythm

disruption

, local

trophic

changes after application)

Glucocorticoids

–

adverse

events

prevention

Slide29

Immunosuppression

- ↑ susceptibility to

infections

,

activation

of

latent infections

- Slow

wound

healing

-

Even

with

local

administration

Supression

of

endogenous

glucocorticoid

production

- Acute

inadequacy

when

suddenly

discontinuing

higher

doses-

Prevention = complete

therapy by gradual dose

reductionOsteoporosis- Risk

only for chronic

therapy- Densitometric

examinationMineralocorticoid

effect- Water

retention and Na +- ↑ TK, loss

of K +

Glucocorticoids

–

adverse events

Slide30

Hyperglycemia

,

steroidal

diabetes

Muscle

weakness

, myopathy, atrophy

Psychotropic effects

Insomnia

, motor

agitation

,

vertigo

,

euphoria

,

depression

Psychic

habit

GIT

Exacerbation of

gastric

ulcer

Intestinal

perforation,

acute pancreatitis

KVS

- HT,

atherosclerosis,

cardiomyopathy, ↑ coagulopathy

, arrhythmia

Glucocorticoids

– adverse

events

Slide31

Eye

Induction

of

glaucoma

(↑

intraocular

pressure)Corneal

ulceration

in keratitis

herpetica

Endocrine

Growth

inhibition

in

children

(

therapy

longer

than

6

months)

Amenorrhea

, potency

and libido decrease

Skin

atrophy

Intradermal

bleedingAcne

, hirsutism

Glucocorticoids – adverse

events

Slide32

Glucocorticoids

–

interactions

Prednisone reduces the plasma levels of salicylates and oral anticoagulants.

The effect of prednisone is reduced by barbiturates, phenytoin, rifampicin.

Slide33

Therapeutic

indications

Diseases of connective tissue, rheumatological

diseases

and

collagenoses

(RA, SLE, SS, DM…)Severe forms of allergic reactionsNon-infectious

inflammatory diseases of the eyeSevere skin disorders

Haematological diseasesMalignant diseasesConditions after organ transplantation

Inflammatory

gastrointestinal

disease

Non-

inflammatory

respiratory

disorders

Renal DiseaseImmunalternative disease in neurologySubstitution therapy for

secondary adrenocortical insufficiencyCongenital adrenal hyperplasia